Generation of B-cells having the potential for autoantibody (antibody against self-antigen) production is common under normal physiological conditions. However, such natural autoantibodies are low affinity IgM antibodies that exhibit wide-spectrum reactivity and strong a preference for soluble self antigens over cell surface antigens (see, e.g., Dichiero et al., J Immunol. 134(2):765-771 (1985); Cote et al., Proc. Natl. Acad. Sci 83:2959-2963 (1986)). Autoreactive low-affinity B-cells undergo apoptosis and, therefore, are unlikely to present a danger to a healthy organism.
In some instances, an increase in the number of autoantibody-producing B cells, their recruitment to specific areas, or an increase in the affinity of the autoantibodies being produced can lead to the development of an autoimmune disease. Certain autoimmune diseases are characterized by the presence of specific autoantibodies that are believed to contribute to the pathogenesis of the disease and maintenance of the disease state.
Sjögren's syndrome (SS) is a rare autoimmune disease, affecting approximately 0.2 to 0.7% of the general population. Typically, it manifests between the ages of forty and sixty years, and has an estimated 9:1 female predilection. Notably, the disease occurs in both primary and secondary forms. The primary form affects the salivary and lacrymal glands predominantly, while the secondary form occurs in conjunction with other autoimmune connective tissue disorders, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Patients with both primary and secondary SS (pSS and sSS, respectively) may have both oral and ophthalmic manifestations of disease. Although SS induced dry mouth (xerostomia) and dry eyes (xerophthalmia) have a significant negative impact on the patient's quality of life, a growing body of literature demonstrates further debilitating aspects of the disease including musculoskeletal, pulmonary, and renal manifestations, skin lesions, leukocytoclastic vasculitis, Raynaud's phenomenon, hematologic complications, liver involvement, and B cell lymphomas. Thus, both forms of the disease pose significant morbidity and mortality for afflicted individuals. See Voulgarelis et al., Arthritis Rheum (1999) 42:1765-1772; García-Carrasco et al., J Rheumatol (2002) 29:726-730; Ramos-Casals et al., Medicine (Baltimore) (2002) 81:281-292; Fox, Lancet (2002) 366:321-331; Ekström et al, Blood (2008) 111:4029-4038; and Delalande et al., Medicine (Baltimore) (2008) 83:280-291. Therefore, a need exists for the development of therapies for the treatment of autoimmune diseases, such as Sjogren's syndrome, and other inflammatory diseases.